Synthesis of sterically congested unsymmetrical 1,2-dicarbonyl radicals through a stepwise approach.

A simplified and stepwise synthetic method for producing sterically congested unsymmetrical 1,2-dicarbonyl radicals was successfully demonstrated including detailed characterization of each radical cation. Using this approach, an aryl- and N-heterocyclic carbene-substituted 1,2-dicarbonyl radical in its neutral form is generated, revealing the stabilizing role of N-heterocyclic carbenes.

IZCp and PZCp: Redox Non-innocent Cyclopentadienyl Ligands as Electron Reservoirs for Sandwich Complexes.

A long-sustained effort of systematic steric and electronic modification of cyclopentadienyl (Cp) ligands has enabled them to find wide-ranging, valuable applications. Herein, we present two novel Cp ligands: imidazolium- and pyrrolinium-substituted zwitterionic Cps (IZCp and PZCp), whose key utility is redox non-innocence─the ability to participate cooperatively with the metal center in redox reactions. Through the simple metalation of ZCps, the Cr(0) and Mo(0) half-sandwich complexes (IZCp)Cr(CO)3, (PZCp)Cr(CO)3, (IZCp)Mo(CO)3, and (PZCp)Mo(CO)3, respectively, as well as the Ru(II) sandwich complexes [(IZCp)RuCp]PF6 and [(PZCp)RuCp]PF6 were prepared. The sandwich complexes were fully characterized and showed by cyclic voltammetry reversible one-electron reduction at E1/2 potentials ranging from -1.7 to -2.7 V vs Fc/Fc+. These values are unusually low and have not been observed with other Cp ligands due to the instability of the reduced complexes. Density functional theory (DFT) calculations for the reduced sandwich derivatives with IZCp and PZCp showed their spin densities to be highly delocalized over their ZCp ligand moieties (70-90%). Electron paramagnetic resonance (EPR) analysis of the isolated K[(PZCp)Mo(CO)3] and (PZCp)RuCp also indicated a high degree of ligand-localized radical character. Thus, the IZCp and PZCp ligands act as electron reservoirs to sustain these sandwich complexes in highly reduced states. At the same time, the CO stretching frequencies of K[(PZCp)Mo(CO)3]: νCO 1871, 1748, and 1699 cm-1, rank the [PZCp]- ligand as the strongest electron-donating Cp ligand among the reported CpMo(CO)3 derivatives, whose νCO > 1746 cm-1. In addition, these redox non-innocent Cps were obtained in high yields and found to be practically air- and moisture-stable, unlike typical Cps.

Synthesis and Structural Characterization of Macrocyclic α-ABpeptoids and Their DNA-Encoded Library.

The first synthesis of macrocyclic α-ABpeptoids with varying lengths is described. X-ray crystal structures reveal that cyclic trimer displays a chair-like conformation with a cct amide sequence and cyclic tetramer has a saddle-like structure with an uncommon cccc amide arrangement. The creation of a DNA-encoded combinatorial library of macrocyclic α-ABpeptoids is described.

Uncovering Nitrosyl Reactivity at N-Heterocyclic Carbene Center.

N-heterocyclic carbenes (NHCs) have garnered much attention due to their unique properties, such as strong σ-donating and π-accepting abilities, as well as their transition-metal-like reactivity toward small molecules. In 2015, we discovered that NHCs can react with nitric oxide (NO) gas to form radical adducts that resemble transition metal nitrosyl complexes. To elucidate the analogy between NHC and transition metal NO adducts, here we have undertaken a systematic investigation of the electron- and proton-transfer chemistry of [NHC-NO]⋅ (N-heterocyclic carbene nitric oxide radical) compounds. We have accessed a suite of compounds, comprised of [NHC-NO]+ , [NHC-NO]- , [NHC-NOH]0 , and [NHC-NHOH]+ species. In particular, [NHC-NO]- was isolated as potassium and lithium ion adducts. Most interestingly, a monomeric potassium [NHC-NO]- compound was isolated with the assistance of 18-crown-6, which is the first instance of a monomeric alkali N-oxyl compound to the best of our knowledge. Our results demonstrate that [NHC-NO]⋅ exhibits redox behavior broadly similar to metal nitrosyl complexes, which opens up more possibilities for utilizing NHCs to build on the known reactivity of metal complexes.

Formation of Highly Stable 1,2-Dicarbonyl Organic Radicals from Cyclic (Alkyl)(amino)carbenes.

Two air-stable organic radicals derived from oxalyl chloride and cAAC were synthesized, resulting in the unexpected formation of a known (amino)(carboxy) radical cation ([2]BF4) and the oxidative formation of a 1,2-dicarbonyl radical cation ([3]BF4) from a neutral 3-oxetanone compound (4). The highly strained and newly discovered 4 was obtained by a single-electron reduction of [3]BF4 with a mild reducing agent. This result differs from the generation of NHC-based 1,2-dicarbonyl radicals, indicating the uniqueness of cAAC.

Revisiting the Reaction of IPr with Tritylium: An Alternative Mechanistic Pathway.

Despite a recent proposal on the mechanism of a single-electron transfer (SET) process between tritylium and 2,6-bis(diisopropylphenyl)imidazol-2-ylidene (IPr) based on evidence of transient IPr radical cation intermediate ([IPr]⋅+ ) formation, such oxidation is still contentious because of the high oxidation potential of N-heterocyclic carbenes. Our experimental analysis indicates that the appearance of deep purple color, previously considered to be from transient [IPr]⋅+ , originates from a zwitterionic intermediate (3 a), not a radical cation. Here, we propose an alternative mechanism for the reaction involving tritylium and IPr. This mechanism is noteworthy for explaining how [NHC-H]+ can be generated without the formation of transient [NHC]⋅+ , which has been frequently proposed as an intermediate for the reaction between NHC and oxidants. These results also show that a transient strong single-electron donor (3 a) could be generated by the alternative mechanism for oxidants using NHCs, which is a more feasible explanation for the reactivity of NHCs with oxidants.

Mechanistic Studies for Pd(II)(O2) Reduction Generating Pd(0) and H2O: Formation of Pd(OH)2 as a Key Intermediate.

Molecular oxygen (O2) remains to be an ideal yet underutilized feedstock for the oxidative transformation of organic substrates and renewable energy systems such as fuel cells. Palladium (Pd) has shown particular promise in enabling these applications. The present study describes a Pd-mediated O2 reduction to water via C-H activation of 9,10-dihydroanthracene (DHA) by a Pd(II) η2-peroxo complex 1O2. The reaction yields stoichiometric anthracene and Pd(0) product 1 and is notable in two respects. First, plots of concentrations of the reaction participants over time have distinctly sigmoidal shapes, indicating that conversion accelerates over time and implying autocatalysis. Second, the reaction proceeds via a genuine monometallic Pd(II) dihydroxide 1(OH)2 directly observed to grow and decay as an intermediate. Confirming its role as an intermediate, the dihydroxide 1(OH)2 was found to mediate C-H oxidation of DHA on par in activity with the peroxo compound 1O2. Mechanistic studies with density functional theory (DFT) calculations suggested that both 1O2 and 1(OH)2 react with DHA by hydrogen atom transfer (HAT) and that autocatalysis in the 1O2 reaction results from oxidative addition of the initial Pd(II) complex 1O2 to the Pd(0) product 1. This reaction forms a transient bis(µ-oxo) Pd(II) dimer 1O21 that is more active in the HAT oxidation of DHA than the initial 1O2.

Persistent Radicals Derived from N-Heterocyclic Carbenes for Material Applications.

Persistent radicals are potential building blocks of novel materials in many fields. Recently, highly stable persistent radicals are considered to be within reach, thanks to several radical stabilization strategies such as spin delocalization and steric protection. N-Heterocyclic carbene (NHC)-derived substituents can be attached to a radical center for these purposes, as illustrated by numerous NHC-stabilized radicals reported in the last two decades.This Account describes our recent work on developing NHC-derived persistent radicals, as well as their prospective applications. Considering that NHCs not only stabilize radicals but also reversibly interact with gas molecules, in 2015 our group reported NHC-nitric oxide (NHC-NO) radicals produced by reversibly trapping nitric oxide (NO) radical gas in NHCs. The resultant compounds were loaded into biocompatible poly(ethylene glycol)-block-poly(caprolactone) (PEG-b-PCL) micelles and injected into tumor-bearing mice. Then, NO release was triggered by high-intensity focused ultrasound irradiation of the tumor tissue. Furthermore, the NHC-NO radicals could also serve as a platform to generate other organic radicals such as oxime ether or iminyl radicals. Apart from medicine-related applications, radicals stabilized by NHCs can be used as energy storage materials. In this context, the triazenyl radical containing two NHC units reported by our laboratory could be a cathode active material in batteries, as an organic alternative to LiCoO2. The subsequently prepared unsymmetrical triazenyl radical derivatives were applied as anolytes in nonaqueous all-organic redox flow batteries. In addition, a ferrocene-based redox flow battery anolyte was obtained by introducing NHC-derived substituents that effectively stabilize the ferrocenate derivatives previously reported only at low temperatures. The batteries containing NHC-supported radicals exhibited high energy efficiency and insignificant radical decomposition over multiple cycles. Finally, toward developing air-persistent organic radicals for flexible devices and MRI contrasting agents, we also highlight our recent air- and physiologically stable organic radicals derived from NHCs. Coordination of tris(pentafluorophenyl)borane to the NHC-NO radical produced a new radical cation that is stable in an organic solvent under air for several months. The readily accessible 1,2-dicarbonyl radical cations generated by the reaction of NHCs with oxalyl chloride are remarkably persistent even in an aqueous solution for several months. They are also highly stable even under physiological conditions, making them particularly attractive potential candidates for organic MRI contrast agents. We hope that this Account will serve as a guide for the future development of stable NHC-derived organic radicals and draw the attention of the synthetic community to their potential applications in material science.

Cobalt-Catalyzed Formation of Grignard Reagents via C-O or C-S Bond Activation.

C(aryl)-OMe bond functionalization catalyzed by cobalt(II) chloride in combination with a nacnac-type ligand and magnesium as a reductant is reported. Borylation and benzoylation of aryl methoxides are demonstrated, and C(aryl)-SMe bond borylation can be achieved under similar conditions. This is the first example of achieving these transformations using cobalt catalysis. Mechanistic studies suggest that a Grignard reagent is generated as an intermediate in a rare example of a magnesiation via a C-O bond activation reaction. Indeed, an organomagnesium species could be directly observed by electrospray ionization mass spectroscopic analysis. Kinetic experiments indicate that a heterogeneous cobalt catalyst performs the C-O bond activation.

Reversible ammonia uptake at room temperature in a robust and tunable metal-organic framework.

Ammonia is useful for the production of fertilizers and chemicals for modern technology, but its high toxicity and corrosiveness are harmful to the environment and human health. Here, we report the recyclable and tunable ammonia adsorption using a robust imidazolium-based MOF (JCM-1) that uptakes 5.7 mmol g-1 of NH3 at 298 K reversibly without structural deformation. Furthermore, a simple substitution of NO3 - with Cl- in a post-synthetic manner leads to an increase in the NH3 uptake capacity of JCM-1(Cl-) up to 7.2 mmol g-1.

Grignard reagent formation via C-F bond activation: a centenary perspective.

Examples of Grignard reagents obtained by C-F bond activation with magnesium have kept appearing in the literature over the last century. Due to the high bond dissociation energy of the C-F bond, a lot of effort has been invested in the preparation of highly active forms of magnesium for this purpose. Originally, magnesium activation was achieved by the application of additives, notably iodine. Later work focused on the generation of highly active magnesium powder by reduction of magnesium salts with alkali metals ("Rieke magnesium"). Modern approaches to the problem involve the application of Mg(I)-Mg(I) dimers and C-F bond activation performed by a transition metal catalyst followed by transmetallation with a magnesium salt. The purpose of this article is to provide an overview of fluoro-Grignard reagent preparation approaches reported to date.

Effects of Natural Versus Synthetic Consonant and Vowel Stimuli on Cortical Auditory-Evoked Potential.

BACKGROUND AND OBJECTIVES: Natural and synthetic speech signals effectively stimulate cortical auditory evoked potential (CAEP). This study aimed to select the speech materials for CAEP and identify CAEP waveforms according to gender of speaker (GS) and gender of listener (GL). SUBJECTS AND METHODS: Two experiments including a comparison of natural and synthetic stimuli and CAEP measurement were performed of 21 young announcers and 40 young adults. Plosive /g/ and /b/ and aspirated plosive /k/ and /p/ were combined to /a/. Six bisyllables-/ga/-/ka/, /ga/-/ba/, /ga/-/pa/, /ka/-/ba/, /ka/-/pa/, and /ba/-/pa/-were formulated as tentative forwarding and backwarding orders. In the natural and synthetic stimulation mode (SM) according to GS, /ka/ and /pa/ were selected through the first experiment used for CAEP measurement. RESULTS: The correction rate differences were largest (74%) at /ka/-/ pa/ and /pa/-/ka/; thus, they were selected as stimulation materals for CAEP measurement. The SM showed shorter latency with P2 and N1-P2 with natural stimulation and N2 with synthetic stimulation. The P2 amplitude was larger with natural stimulation. The SD showed significantly larger amplitude for P2 and N1-P2 with /pa/. The GS showed shorter latency for P2, N2, and N1-P2 and larger amplitude for N2 with female speakers. The GL showed shorter latency for N2 and N1-P2 and larger amplitude for N2 with female listeners. CONCLUSIONS: Although several variables showed significance for N2, P2, and N1-P2, P1 and N1 did not show any significance for any variables. N2 and P2 of CAEP seemed affected by endogenous factors.

Construction of Stable Metal-Organic Framework Platforms Embedding N-Heterocyclic Carbene Metal Complexes for Selective Catalysis.

We report a bottom-up approach to immobilize catalysts into MOFs, including copper halides and gold chloride in a predictable manner. Interestingly, the structures of MOFs bearing NHC metal complexes maintained a similar 4-fold interpenetrated cube. They exhibited exceptionally high porosity despite the interpenetrated structure and showed good stability in various solvents. Moreover, these MOFs possess high size activity depending on the size of the substrates in various reactions, compared to homogeneous catalysis. Also, the high catalytic activity of MOFs can be preserved 4 times without significant loss of crystallinity. Incorporation of the various metal complexes into MOFs allows for the preparation of functional MOFs for practical applications.

Generation of N-H Imines from α-Azidocarboxylic Acids through Ru-Catalyzed Decarboxylation.

A new method for the synthesis of N-H imines from α-azidocarboxylic acids was developed, which proceeds through decarboxylative C-C bond cleavage catalyzed by a commercial diruthenium complex ([CpRu(CO)2]2) under visible light irradiation at room temperature within several minutes. The reactive products undergo condensation, which forms cyclic trimers (2,4,6-trialkylhexahydro-1,3,5-triazines) or linear N,N'-bis(arylmethylidene)arylmethanediamines in quantitative yields. Alternatively, the N-H imines can be trapped with benzylamine and 2-(aminomethyl)aniline, providing stable N-benylimines and tetrahydroquinazolines, respectively. Subsequent oxidation of tetrahydroquinazolines produced quinazolines.

Reduction of highly bulky triphenolamine molybdenum nitrido and chloride complexes.

Transition metal nitrides are key intermediates in the catalytic reduction of dinitrogen to ammonia. To date, transition metal nitride complexes with the triphenolamine (TPA) ligand have not been reported and the system with the ligand has been much less studied for ammonia formation compared with other systems. Herein, we report a series of molybdenum complexes supported by a sterically demanding TPA ligand, including a nitrido complex NMo(TPA). We achieved the stoichiometric conversion of the nitride moiety into ammonia under ambient conditions by adding proton and electron sources to NMo(TPA). However, the catalytic turnover for N2 reduction to ammonia was not observed in the triphenolamine ligand system unlike the Schrock system-triamidoamine ligand. Density functional theory calculation revealed that the molybdenum center favors binding NH3 over N2 by 16.9 kcal mol-1 and the structural lability of the trigonal bipyramidal (TBP) molybdenum complex seems to prevent catalytic turnover. Our systematic study showed that the electronegativity and bond length of ancillary ligands determine the preference between N2 and NH3, suggesting a systematic design strategy for improvement.

Deeper Understanding of Mononuclear Manganese(IV)-Oxo Binding Brønsted and Lewis Acids and the Manganese(IV)-Hydroxide Complex.

Binding of Lewis acidic metal ions and Brønsted acid at the metal-oxo group of high-valent metal-oxo complexes enhances their reactivities significantly in oxidation reactions. However, such a binding of Lewis acids and proton at the metal-oxo group has been questioned in several cases and remains to be clarified. Herein, we report the synthesis, characterization, and reactivity studies of a mononuclear manganese(IV)-oxo complex binding triflic acid, {[(dpaq)MnIV(O)]-HOTf}+ (1-HOTf). First, 1-HOTf was synthesized and characterized using various spectroscopic techniques, including resonance Raman (rRaman) and X-ray absorption spectroscopy/extended X-ray absorption fine structure. In particular, in rRaman experiments, we observed a linear correlation between the Mn-O stretching frequencies of 1-HOTf (e.g., νMn-O at ∼793 cm-1) and 1-Mn+ (Mn+ = Ca2+, Zn2+, Lu3+, Al3+, or Sc3+) and the Lewis acidities of H+ and Mn+ ions, suggesting that H+ and Mn+ bind at the metal-oxo moiety of [(dpaq)MnIV(O)]+. Interestingly, a single-crystal structure of 1-HOTf was obtained by X-ray diffraction analysis, but the structure was not an expected Mn(IV)-oxo complex but a Mn(IV)-hydroxide complex, [(dpaq)MnIV(OH)](OTf)2 (4), with a Mn-O bond distance of 1.8043(19) Å and a Mn-O stretch at 660 cm-1. More interestingly, 4 reverted to 1-HOTf upon dissolution, demonstrating that 1-HOTf and 4 are interconvertible depending on the physical states, such as 1-HOTf in solution and 4 in isolated solid. The reactivity of 1-HOTf was investigated in hydrogen atom transfer (HAT) and oxygen atom transfer (OAT) reactions and then compared with those of 1-Mn+ complexes; an interesting correlation between the Mn-O stretching frequencies of 1-HOTf and 1-Mn+ and their reactivities in the OAT and HAT reactions is reported for the first time in this study.

Pyrrolinium-Substituted Persistent Zwitterionic Ferrocenate Derivative Enabling the Application of Ferrocene Anolyte.

Here, we report the imidazolium-/pyrrolinium-substituted persistent zwitterionic ferrocenate derivatives, which were characterized by electron paramagnetic resonance (EPR) and 57Fe Mössbauer spectroscopy. Additional theoretical studies on these zwitterionic ferrocenate derivatives clearly explain the origin of their thermal stability and the orbital interactions between iron and imidazolium-/pyrrolinium-substituted zwitterionic cyclopentadienyl ligand. Exploiting the facile Fe(II/I) redox chemistry, we successfully demonstrated that the pyrrolinium-substituted ferrocene derivative can be applied as an example of derivatized ferrocene anolyte for redox-flow batteries. These zwitterionic ferrocenate derivatives will not only deepen our understanding of the intrinsic chemistry of ferrocenate but have the potential to open the way for the rational design of metallocenate derivatives for various applications.

Fixation of Dinitrogen at an Asymmetric Binuclear Titanium Complex.

A new type of dititanium dinitrogen complex supported by a triphenolamine (TPA) ligand is reported. Analysis by single-crystal X-ray diffraction and Raman and NMR spectroscopy reveals different coordination geometries for the two titanium centers. Hence, coordination of TPA and a nitrogen ligand results in trigonal-bipyramidal geometry, while an octahedral titanium center is obtained upon additional coordination of an ethoxide generated upon C-O bond cleavage in a diethyl ether solvent molecule. The titanium complex successfully generates ammonia in the presence of an excess amount of PCy3HI and KC8 in 154% yield (per titanium atom). A titanium complex with a bulkier TPA does not form a dinitrogen complex, and mononuclear titanium dinitrogen complexes were not accessible, presumably because of the high tendency of early transition metals to form binuclear dinitrogen complexes.

Antitumor Effect of Metformin in Combination with Binimetinib on Melanoma Cells.

Cutaneous melanoma is a fatal disease for patients with distant metastasis. Metformin is the most widely used anti-diabetic drug, and proved to suppress cell proliferation and metastasis in diverse cancers including melanoma. We previously reported that MEK inhibitor trametinib increases the expression of epithelial-mesenchymal transition (EMT) regulators and melanoma cell motility, which are suppressed by addition of metformin in A375 melanoma cells. To confirm our findings further, we first evaluated the effect of metformin in combination with another MEK inhibitor binimetinib on cell viability in G361 melanoma cells. We then investigated whether binimetinib affects the expression of EMT regulators and cell motility. We finally monitored the effect of metformin on binimetinib-induced cell migration. Cell viability assay showed that combination index (CI) value at ED50 is 0.80, suggesting synergy for the combination of metformin with binimetinib. Our results also revealed that binimetinib increased the expression of EMT regulators such as integrin αV, fibronectin and slug, which correlate well with the enhanced cell migration in wound healing assay. Metformin, on the contrary, suppressed the expression of sparc, integrin αV, fibronectin and N-cadherin with the reduced cell motility. The combination treatment showed that metformin counteracts the binimetinib-induced increase of cell motility. Overall, these results suggest that metformin with binimetinib might be useful as a potential therapeutic adjuvant against cell survival and metastatic activity in melanoma patients.

Theoretical Assessment of Dinitrogen Fixation on Carbon Atom.

Dinitrogen activation in non-metallic systems has received considerable attention in recent years. Herein, we report the theoretical feasibility of N2 fixation using aminocarbenes (L) or their anionic derivatives. The molecular descriptors of L and anionic L- , which affect the interaction of L and anionic L- with N2 , were identified through multiple linear regression analysis. Additionally, the electron flow during C-N bond formation was confirmed by performing intrinsic reaction coordination calculations with intrinsic bond orbital analysis for the reaction of anionic L- with N2 .